Nutrients 2015, 7, 8020-8035; doi:10.

3390/nu7095380
OPEN ACCESS

nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review

Lactose Intolerance in Adults: Biological Mechanism and

Dietary Management
Yanyong Deng 1 , Benjamin Misselwitz 2 , Ning Dai 1 and Mark Fox 2,3, *

1
Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, 3 East Qingchun Road, 310016 Hangzhou, China;
E-Mails: dengyanyong@163.com (Y.D.); ndaicn@yahoo.com (N.D.)
2
Neurogastroenterology and Motility Research Group, Department of Gastroenterology and
Hepatology, Division of Gastroenterology & Hepatology, University Hospital Zrich,
Zrich CH-8091, Switzerland; E-Mail: benjamin.misselwitz@usz.ch
3
Division of Gastroenterology, St. Claraspital, 4058 Basel, Switzerland

* Author to whom correspondence should be addressed; E-Mail: dr.mark.fox@gmail.com;

Tel.: +41-791934795.

Received: 14 July 2015 / Accepted: 14 September 2015 / Published: 18 September 2015

Abstract: Lactose intolerance related to primary or secondary lactase deficiency is

characterized by abdominal pain and distension, borborygmi, flatus, and diarrhea induced
by lactose in dairy products. The biological mechanism and lactose malabsorption is
established and several investigations are available, including genetic, endoscopic and
physiological tests. Lactose intolerance depends not only on the expression of lactase
but also on the dose of lactose, intestinal flora, gastrointestinal motility, small intestinal
bacterial overgrowth and sensitivity of the gastrointestinal tract to the generation of gas
and other fermentation products of lactose digestion. Treatment of lactose intolerance can
include lactose-reduced diet and enzyme replacement. This is effective if symptoms are only
related to dairy products; however, lactose intolerance can be part of a wider intolerance to
variably absorbed, fermentable oligo-, di-, monosaccharides and polyols (FODMAPs). This
is present in at least half of patients with irritable bowel syndrome (IBS) and this group
requires not only restriction of lactose intake but also a low FODMAP diet to improve
gastrointestinal complaints. The long-term effects of a dairy-free, low FODMAPs diet on
nutritional health and the fecal microbiome are not well defined. This review summarizes
recent advances in our understanding of the genetic basis, biological mechanism, diagnosis
and dietary management of lactose intolerance.
Nutrients 2015, 7 8021

Keywords: lactose intolerance; lactase deficiency; lactose malabsorption; FODMAP;

genetic test; hydrogen breath test; irritable bowel syndrome

1. Lactose and Lactase

Lactose is a disaccharide consisting of galactose bound to glucose and is of key importance in animal
life as the main source of calories from milk of all mammals, all except the sea lion. Intestinal absorption
of lactose requires hydrolysis to its component monosaccharides by the brush-border enzyme lactase.
From week 8 of gestation, lactase activity can be detected at the mucosal surface in the human intestine.
Activity increases until week 34 and lactase expression is at its peak by birth. The ability to digest
lactose during the period of breast-feeding is essential to the health of the infant as demonstrated by
congenital lactase deficiency that is fatal if not recognized very early after birth. However, following the
first few months of life, lactase activity starts to decrease (lactase non-persistence). In most humans, this
activity declines following weaning to undetectable levels as a consequence of the normal maturational
down-regulation of lactase expression [1]. The exceptions to this rule are the descendants of populations
that traditionally practice cattle domestication maintain the ability to digest milk and other dairy products
into adulthood. The frequency of this lactase persistence trait is high in northern European populations
(>90% in Scandinavia and Holland), decreases in frequency across southern Europe and the Middle East
(~50% in Spain, Italy and pastoralist Arab populations) and is low in Asia and most of Africa (~1% in
Chinese, ~5%20% in West African agriculturalists); although it is common in pastoralist populations
from Africa (~90% in Tutsi, ~50% in Fulani) [2].

2. Genetics of Lactase Persistence

Lactase persistence is thought to be related to the domestication of dairy cattle during the last
10,000 years. Lactase persistence is inherited as a dominant Mendelian trait [3]. Adult expression of
the gene encoding lactase (LCT), located on 2q21 appears to be regulated by cis-acting elements [4].
A linkage disequilibrium (LD) and haplotype analysis of Finnish pedigrees identifies two single
single nucleotide polymorphisms (SNPs) associated with the lactase persistence trait: C/T-13910 and
G/A-22018, located ~14 kb and ~22 kb upstream of LCT, respectively, within introns 9 and 13 of the
adjacent minichromosome maintenance 6 (MCM6) gene [3]. The T-13910 and A-22018 alleles are 100%
and 97% associated with lactase persistence, respectively, in the Finnish study, and the T-13910 allele
is ~86%98% associated with lactase persistence in other European populations [57]. The genotype in
China is C/C-13910, and no SNP associated with lactase persistence has been identified in the lactase
gene regulatory sequence [8,9]. However, there are several lactase gene single nucleotide polymorphisms
of this kind in other populations. Lactase persistence is mediated by G-13915 in Saudi Arabia [10],
in African tribes by the G-14010, G-13915, and G-13907 polymorphism (Figure 1) [11,12]. Thus,
lactase persistence developed several times independently in human evolution in different areas of the
world [11]. Multiple independent variants have allowed various human populations to quickly modify
LCT expression and have been strongly conserved in adult milk-consuming populations, emphasizing the
importance of regulatory mutations in recent human evolution [13]. In adult patients with homozygous
Nutrients 2015,
Nutrients 2015, 77 80223

with homozygous
lactase persistence,lactase
enzyme persistence, enzyme
levels at the jejunallevels
brushatborder
the jejunal brush border
are 10-times arethan
higher 10-times higherwith
for patients than
for patients with
homozygous homozygousand
non-persistence, non-persistence,
heterozygousand heterozygous
individuals [14]. individuals [14].

Figure 1. Map of the lactase (LCT) and minichromosome maintenance 6 (MCM6) gene
Figureand
region 1. Map of the
location lactase (LCT)
of genotyped singleand minichromosome
nucleotide maintenance
polymorphisms (SNPs).6(a)
(MCM6) gene
Distribution
region
of 123 SNPsand included
locationin genotype
of genotyped
analysis;single
(b) mapnucleotide
of the LCT polymorphisms
and MCM6 gene (SNPs).
region;
(c) map of the MCM6 gene; and (d) location of lactase persistence-associated SNPs MCM6
(a) Distribution of 123 SNPs included in genotype analysis; (b) map of the LCT and within
gene region; (c) map of the MCM6 gene; and (d) location of lactase
introns 9 and 13 of the MCM6 gene in African and European populations [12]. persistence-associated
SNPs within introns 9 and 13 of the MCM6 gene in African and European populations [12].
3. Biological Mechanism of Lactose Intolerance
3. Biological Mechanism of Lactose Intolerance
About two thirds of the Worlds population undergoes a genetically programmed decrease in lactase
About two thirds of the Worlds population undergoes a genetically programmed decrease in lactase
synthesis after weaning (primary lactase deficiency) [15,16]. Additionally, in individuals with lactase
synthesis after weaning (primary lactase deficiency) [15,16]. Additionally, in individuals with lactase
persistence the occurrence of gastrointestinal infection, inflammatory bowel disease, abdominal surgery
persistence the occurrence of gastrointestinal infection, inflammatory bowel disease, abdominal surgery
and other health issues can also cause a decrease in lactase activity (secondary lactase deficiency). Both
and other health issues can also cause a decrease in lactase activity (secondary lactase deficiency). Both
conditions must be distinguished from congenital lactase deficiency, which is an extremely rare disease
conditions must be distinguished from congenital lactase deficiency, which is an extremely rare disease
of infancy with approximately 40 cases having been reported, mainly in Finland [2].
of infancy with approximately 40 cases having been reported, mainly in Finland [2].
Whatever the cause, lactase deficiency results in unabsorbed lactose being present in the intestinal
Whatever the cause, lactase deficiency results in unabsorbed lactose being present in the intestinal
tract, which has effects that can lead to symptoms of lactose intolerance in susceptible individuals [17].
tract, which has effects that can lead to symptoms of lactose intolerance in susceptible individuals [17].
First, the increased osmotic load increases the intestinal water content. Second, lactose is readily
First, the increased osmotic load increases the intestinal water content. Second, lactose is readily
fermented
fermented by
by the
the colonic
colonic microbiome
microbiome leading
leading toto production
production of of short
short chain
chain fatty
fatty acids
acids and
and gas
gas (mainly
(mainly
hydrogen (H 2 ), carbon dioxide (CO 2 ), and methane (CH 4 )). These biological
hydrogen (H2), carbon dioxide (CO2), and methane (CH4)). These biological processes are presentprocesses are present
also
also for other poorly-absorbed, fermentable oligosaccharides, disaccharides, monosaccharides,
for other poorly-absorbed, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols and
polyols (FODMAPs)
(FODMAPs) that arethatubiquitous
are ubiquitous
in the in the
dietdiet [18,19].
[18,19]. Double-blind,cross-over
Double-blind, cross-overstudies
studies in
in healthy
healthy
volunteers
volunteers applied scintigraphy or magnetic resonance imaging to document oro-cecal transit time
applied scintigraphy or magnetic resonance imaging to document oro-cecal transit time
together
together with breath testing to assess fermentation of the substrate. Fructose (a disaccharide similar to
with breath testing to assess fermentation of the substrate. Fructose (a disaccharide similar to
lactose) was seen to increase small bowel water, accelerate oro-caecal transit time (OCTT) and trigger a
Nutrients 2015, 7 4
Nutrients 2015, 7 8023

lactose) was seen to increase small bowel water, accelerate oro-caecal transit time (OCTT) and trigger
sharp increase
a sharp in breath
increase hydrogen
in breath production
hydrogen (Figure
production 2), whereas
(Figure 30 g glucose
2), whereas 30 g (a well-absorbed
glucose control)
(a well-absorbed
had no effect
control) had [20,21].
no effectIt[20,21].
should be It noted
shouldthatbe these
notedeffects are seen
that these for are
effects poorly-absorbed, fermentable
seen for poorly-absorbed,
disaccharides both in healthboth
fermentable disaccharides andinin health
patientsandwith gastrointestinal
in patients disease [2224].
with gastrointestinal Long-chain
disease [2224].
carbohydrates (e.g., fructans, cellulose (dietary fiber)) that are not digested or absorbed
Long-chain carbohydrates (e.g., fructans, cellulose (dietary fiber)) that are not digested or absorbed by the small
intestine haveintestine
by the small less impacthaveonless
small bowel
impact ontransit
small than
bowel short-chain
transit than carbohydrates; however, fermentation
short-chain carbohydrates; however,
of this material in the large bowel produces similar effects on colonic function
fermentation of this material in the large bowel produces similar effects on colonic function [21].[21].
Malabsorption
Malabsorptionisis aa necessary
necessary precondition
precondition for forlactose
lactoseororFODMAP
FODMAPintolerance;
intolerance; however,
however, thethe
twotwo
are
are not synonymous and the causes of symptoms must be considered separately
not synonymous and the causes of symptoms must be considered separately [25]. The threshold for [25]. The threshold
for dietary
dietary lactose
lactose tolerance
tolerance is dependent
is dependent on several
on several factors factors including
including the consumed,
the dose dose consumed,
residualresidual
lactase
lactase expression [2], ingestion with other dietary components [26], gut-transit
expression [2], ingestion with other dietary components [26], gut-transit time, small bowel bacterial time, small bowel
bacterial
overgrowthovergrowth
[22,23], [22,23],
and also and also composition
composition of themicrobiome
of the enteric enteric microbiome
(e.g., high(e.g., highfermenters,
vs. low vs. low
fermenters,
hydrogen vs. hydrogen methane [25,2729].
methanevs.producers) producers) In [25,2729].
addition toInthese addition to these environmental
environmental and physiological and
physiological
factors, it hasfactors, it has been
been shown that shown
patientsthat patients
with withbowel
irritable irritable bowel syndrome
syndrome are at particular
are at particular risk of risk
both
of both self-reporting dairy intolerance [9,30] and experiencing symptoms after
self-reporting dairy intolerance [9,30] and experiencing symptoms after lactose and FODMAP ingestion lactose and FODMAP
ingestion
[31,32]. [31,32].

Figure 2. Small bowel water content (SBWC) and breath hydrogen (H2) concentrations
Figure 2. Small bowel water content (SBWC) and breath hydrogen (H2) concentrations after
after drinking each of the drinks: glucose and fructose. The time of drinking (t = 0 min) is
drinking each of the drinks: glucose and fructose. The time of drinking (t = 0 min) is
highlighted in the chart. Values of SBWC are mean volume (mL) s.e.m (standard error
highlighted in the chart. Values of SBWC are mean volume (mL) s.e.m (standard error of
of mean). Values of H2 are mean concentration (p.p.m.) s.e.m. Figure modified from
mean). Values of H2 are mean concentration (p.p.m.) s.e.m. Figure modified from
Murray et al. [21].
Murray et al. [21].

Symptoms
Symptomsof oflactose
lactoseintolerance
intolerancegenerally
generallydodonot
notoccur
occuruntil
untilthere
thereisisless
lessthan
than50%
50%of oflactase
lactaseactivity.
activity.
Regular
Regular lactose intake may also have an effect. Although lactase expression is not up-regulated by
lactose intake may also have an effect. Although lactase expression is not up-regulated by
lactose
lactoseingestion,
ingestion,tolerance
tolerancecould
couldbe
beinduced
inducedby byadaptation
adaptationofofthe
theintestinal
intestinalflora
flora[26].
[26]. Further,
Further, most
most
people
peoplewith
with lactase
lactase non-persistence
non-persistence can tolerate small
can tolerate small amounts
amounts ofoflactose
lactose(less
(lessthan
than1212g,g,equivalent
equivalentto
to one cup), especially when it is combined with other foods or spread throughout the day [26,33].
 Nutrients 2015, 7 5
Nutrients 2015, 7 8024
one cup), especially when it is combined with other foods or spread throughout the day [26,33]. A
Adouble-blinded,
double-blinded,randomized,
randomized, three-way cross over
three-way cross overcomparison
comparisonof lactose
of lactose tolerance
tolerance testingtesting
at 10 g,at
10gg,and
20 20 g40andg 40 g lactose
lactose waswas performed
performed in patients
in patients withwith diarrheapredominant
diarrhea predominantirritable
irritablebowel
bowelsyndrome
syndrome
(IBS-D)and
(IBS-D) andcontrols
controls in in aa Chinese
Chinese population
population withwith lactase
lactase deficiency
deficiency [31].
[31]. The
Thestudy
studydesign
designincluded
includeda
adose
dosebelow
belownormal
normalsymptom
symptomthreshold
threshold(10(10g),g),plus
plusa dose reflecting
a dose reflectingnormal
normalintake
intakeat aatsingle
a singlemeal
meal(20
g) and
(20 a positive
g) and a positivecontrol suchsuch
control as that usedused
as that in epidemiological trials trials
in epidemiological (40 g).(40The g).multiple-dose
The multiple-dosemethod
(Figure (Figure
method 3) not only3) notdemonstrates the effectthe
only demonstrates of effect
dose inof both
dosestudy
in bothgroups,
studybut also guides
groups, but also nutritional
guides
nutritional management in a given patient. Importantly, the risk of symptoms in this study was greatlyin
management in a given patient. Importantly, the risk of symptoms in this study was greatly increased
IBS-D patients,
increased in IBS-D especially
patients,at especially
low-moderate doses found indoses
at low-moderate the diet
found[31].
in Indeed,
the dietfew[31].healthy
Indeed,controls
few
with lactase non-persistence reported gastrointestinal (GI) symptoms except
healthy controls with lactase non-persistence reported gastrointestinal (GI) symptoms except at the at the 40 g lactose dose
[31].
40 IBS patients
g lactose dose are known
[31]. IBStopatients
be morearesensitive
knowntotoa variety
be moreof sensitive
dietary and to physical
a varietyinterventions
of dietary and that
distend the
physical GI tract [34].
interventions that Further studies
distend the in the[34].
GI tract sameFurther
Chinese population
studies in the demonstrated
same Chinesethat anxiety,
population
visceral hypersensitivity (defined by rectal barostat) and high-levels of gas production on breath tests
demonstrated that anxiety, visceral hypersensitivity (defined by rectal barostat) and high-levels of gas
are associated with patient reports of symptoms after ingestion of a modest (20 g) dose of lactose [35].
production on breath tests are associated with patient reports of symptoms after ingestion of a modest
Heightened sensitivity to distension was associated with abdominal pain, bloating and overall symptom
(20 g) dose of lactose [35]. Heightened sensitivity to distension was associated with abdominal pain,
severity. Excessive gas production contributed to digestive symptoms, especially bloating and
bloating and overall symptom severity. Excessive gas production contributed to digestive symptoms,
borborygmi [35]. Very interestingly, the same group of IBS patients that had lactose intolerance on
especially bloating and borborygmi [35]. Very interestingly, the same group of IBS patients that had
hydrogen breath testing also had heightened activity of the innate mucosal immune system with
lactose intolerance on hydrogen breath testing also had heightened activity of the innate mucosal immune
increased counts of mast cells, intraepithelial lymphocytes and enterochrommafin cells in the terminal
system with increased counts of mast cells, intraepithelial lymphocytes and enterochrommafin cells in
ileum and right colon (Figure 4), with release of pro-inflammatory cytokines after lactose ingestion [36].
the terminal ileum and right colon (Figure 4), with release of pro-inflammatory cytokines after lactose
These observations are similar to those seen in patients with post-infective IBS and provide insight into
ingestion [36]. These observations are similar to those seen in patients with post-infective IBS and
the pathophysiological basis of food intolerance [37].
provide insight into the pathophysiological basis of food intolerance [37].

Figure 3. Prevalence of lactose malabsorption (LM) and lactose intolerance (LI) in patients
Figure
with 3. Prevalence
diarrhea of lactose
predominant malabsorption
irritable (LM) (IBS-D)
bowel syndrome and lactose
andintolerance
controls at(LI)
10-,in20-,
patients
and
withlactose
40-g diarrhea predominant
hydrogen breathirritable bowel*syndrome
test (HBTs). (IBS-D)
p < 0.05; ** and[31].
p < 0.01 controls at 10-, 20-, and
40-g lactose hydrogen breath test (HBTs). * p < 0.05; ** p < 0.01 [31].
Another condition that may play a role in food tolerance is small intestinal bacterial overgrowth
Another condition that may play a role in food tolerance is small intestinal bacterial overgrowth
(SIBO) caused by abnormally high bacterial counts in the small intestine, exceeding 5
105
(SIBO) caused by abnormally high bacterial counts in the small intestine, exceeding 10 organisms/mL
organisms/mL [38]. SIBO is clinically characterized by bloating, abdominal discomfort and diarrhea,
Nutrients 2015, 7 6
Nutrients 2015, 7 8025
[38]. SIBO is clinically characterized by bloating, abdominal discomfort and diarrhea, symptoms that
symptoms
are that are veryto
very comparable comparable
those of to those of
lactose lactose intolerance
intolerance [39]. Bacterial
[39]. Bacterial fermentation
fermentation of lactose
of lactose with
with production
production of short-chain
of short-chain fatty and
fatty acids acidsgas
andin gas
the in the bowel
small small may
bowelbemay be particularly
particularly likely tolikely to
trigger
trigger abdominal
abdominal symptoms.
symptoms. Consistent
Consistent with thiswith this hypothesis,
hypothesis, combined combined scintigraphy
scintigraphy andtest
and breath breath test
studies
showed a higher
studies showed prevalence
a higher of SIBO
prevalence in IBS
of SIBO patients
in IBS with
patients lactose
with intolerance
lactose intolerancethan
thaninin the
the lactose
malabsorption control group [22]. This effect appeared to be independent of oro-caecal transit time and
visceral sensitivity [22].

Figure 4. Representative photomicrographs showing tryptase positive mast cells (MCs) in

Figure 4. Representative photomicrographs showing tryptase positive mast cells (MCs) in
the colonic mucosa of a healthy control (HCs) (ac); an diarrhea predominant irritable bowel
the colonic mucosa of a healthy control (HCs) (ac); an diarrhea predominant irritable bowel
syndrome (IBS-D) patient with lactose malabsorption (LM) (df) and a patient with lactose
syndrome (IBS-D) patient with lactose malabsorption (LM) (df) and a patient with lactose
intolerance (LI) (gi). IBS-D patients with LI had increased mucosal MCs compared with
intolerance (LI) (gi). IBS-D patients with LI had increased mucosal MCs compared with
LM and HCs [36].
LM and HCs [36].

4. Clinical
4. Clinical Diagnosis
Diagnosis of
of Lactose
Lactose Malabsorption
Malabsorption and
and Intolerance
Intolerance

Problems with
Problems with lactose
lactoseabsorption
absorptionhave
havebeen
beendescribed,
described, detected
detected andand diagnosed
diagnosed in several
in several waysways
and
and can
this this lead
can to
lead to confusion
confusion amongamong
doctorsdoctors and patients
and patients [26]. deficiency
[26]. Lactase Lactase deficiency
is definedisasdefined
markedlyas
markedlybrush-border
reduced reduced brush-border lactase
lactase activity activity
relative relative
to the to observed
activity the activity observed
in infants. in infants.
Lactose Lactose
malabsorption
malabsorption
occurs when aoccurs when aamount
substantial substantial amount isof not
of lactose lactose is not absorbed
absorbed in the intestine.
in the intestine. Because Because
lactose
lactose malabsorption
malabsorption is nearlyisalways
nearly attributable
always attributable
to lactaseto deficiency,
lactase deficiency, the presence
the presence of this condition
of this condition can be
can be inferred
inferred from measurements
from measurements of lactose
of lactose malabsorption
malabsorption such assuch as an increase
an increase of glucose
of glucose in the in the blood
blood or an
or an increase of hydrogen in the breath. The term lactose intolerance is defined
increase of hydrogen in the breath. The term lactose intolerance is defined by patient reports of by patient reports
of abdominal
abdominal pain,
pain, bloating,
bloating, borborygmi,
borborygmi, andand diarrhea
diarrhea induced
induced by lactose.
by lactose. Less Less
oftenoften
it canitpresent
can present
with
with nausea or constipation and a range of systemic symptoms, including headaches, fatigue, loss of
 Nutrients 2015, 7 7
Nutrients 2015, 7 8026
nausea or constipation and a range of systemic symptoms, including headaches, fatigue, loss of
concentration, muscle and joint pain, mouth ulcers, and urinary difficulties [40,41]; however, it is unclear
concentration, muscle and joint pain, mouth ulcers, and urinary difficulties [40,41]; however, it is unclear
whether these atypical symptoms are directly due to lactose ingestion, or related to the presence of
whether these atypical symptoms are directly due to lactose ingestion, or related to the presence of
so-called functional diseases, such as irritable bowel syndrome (IBS), which is often accompanied by
so-called functional diseases, such as irritable bowel syndrome (IBS), which is often accompanied
multiple somatic complaints. Certainly, it is not possible to make a definitive diagnosis on clinical
by multiple somatic complaints. Certainly, it is not possible to make a definitive diagnosis on clinical
presentation alone because double-blind trials have shown that the association of self-reported lactose
presentation
intolerancealone
and thebecause double-blind
occurrence trials have
of symptoms after shown
lactose that the association
ingestion of self-reported
are very poor [42], even inlactose
patients
intolerance and the occurrence of symptoms
with lactase deficiency (Figure 5) [9]. after lactose ingestion are very poor [42], even in patients
with lactase deficiency (Figure 5) [9].

Figure 5. Lack of agreement between objective and subjective assessment of lactose

intolerance
Figure 5.[9].
Lack of agreement between objective and subjective assessment of lactose
intolerance [9].
There are various methods (Table 1) for diagnosing lactose malabsorption and intolerance [25].
There
Testing are various
of lactase activitymethods (Table
in mucosal 1) forfrom
biopsies diagnosing lactoseis malabsorption
the duodenum regarded as theand intolerance
reference [25].
standard
forTesting
primaryof and
lactase activity lactase
secondary in mucosal biopsies[43],
deficiency fromhowever,
the duodenum is regarded
limitations as the reference
include standard
inhomogeneous
for primary
expression and secondary
of lactase [44] and lactase deficiencyof[43],
the invasiveness however,
the test. Genetic limitations
tests mayinclude thefor
be useful inhomogeneous
identifying
expression
lactase of lactase
persistence [44]European
in some and the invasiveness
populations of as the
the test. Genetic
T-13910 tests
allele may be useful
is ~86%98% for identifying
associated with
lactasepersistence
lactase persistenceininEuropean
some European populations
populations [57], as the T-13910
however allele is
other SNPs are~86%98%
present in associated
Arabian and with
lactasepopulations
African persistence[1012].
in European
Futurepopulations
genetic tests[57],
will however
likely coverother SNPsofare
a range present
genetic in Arabian and
polymorphisms,
African populations
potentially eliminating [1012]. Future genetic
this limitation. A furthertests will likely
limitation coverbiopsy
of both a rangeandofgenetic
genetictests
polymorphisms,
is that no
potentially
assessment ofeliminating
symptoms isthis limitation.
made. A further
This impacts limitation
on the of both biopsy
clinical relevance andinvestigations
of these genetic testsbecause,
is that no
as assessment of symptoms
addressed above, only a is made. This
proportion of impacts
patients on thelactase
with clinicaldeficiency
relevancedevelop
of theseabdominal
investigations because,
symptoms
as addressed
after above, [31].
ingesting lactose only a proportion of patients with lactase deficiency develop abdominal symptoms
after ingesting lactose [31].
Nutrients 2015, 7 8027

Table 1. Summary of tests for lactose malabsorption and lactose tolerance [25].

Lactose Lactase Activity

H2 -Breath Test Genetic
Tolerance at Jejunal Brush
[17,45] Test [3,12]
Test [46] Border [43,44]

Increase of H2 in
Enzymatic activity
respiratory air Increase of blood sugar Genetic-13910C/T
Test principle of lactase enzyme
after lactose after lactose challenge polymorphism
in biopsy sample
challenge
C:C13910
>20 ppm within 3 <1.1 mmol/L
Cut off lactase <1720 IU/g
h within 3 h
non-persistence
Availability Good Excellent Variable Rare
Rapid GI-transit,
False positives Rapid GI-transit,
small-intestinal Rare (<5%) in
(incorrect impaired glucose Probably rare
bacterial Caucasians
diagnosis) tolerance
overgrowth
All causes of
False negatives Non-H2 -producers.
Fluctuations in secondary Patchy enzyme
malabsorption Full colonic
blood sugar lactose expression
wrongly excluded adaptation
malabsorption
Cannot be
Can be excluded
excluded, kinetic Cannot Cannot be
Secondary causes (histopathology at
of H2 -increase be excluded excluded
same procedure)
can be suggestive
Symptom
Possible Possible Not possible Not possible
assessment
Definitive in
Caucasians.
Method of choice Reference standard
Less in other
for assessment of Rarely performed due for detection of
populations. Not
Comment lactose to inferior sensitivity lactase deficiency
suitable in
malabsorption and specificity (primary or
secondary
and intolerance secondary)
lactase
deficiency.
Cost Low Lowest High Highest

Lactose digestion and the association of maldigestion with symptoms can be assessed by the H2 -breath
test [45] and the lactose tolerance test [46]; however, the former is confounded by fluctuations of
postprandial blood sugar. The H2 -breath test can be false positive in the presence of small intestinal
bacterial overgrowth; however, a larger problem is false-negative tests due to the presence of hydrogen
non-producing bacteria in the colon (2%43%) [17]. This problem of hydrogen non-production can
be mitigated to some extent by examining patient reports of symptoms after the test dose. Patients
Nutrients 2015, 7 8028

with false positive breath tests complain of symptoms directly after ingestion. Those with true
positive lactose intolerance complain of symptoms only after the substrate has entered the colon (usually
50100 min). Another possibility is to combine the biopsy or genetic test (in Caucasians) with the
H2 -breath test; however, this is an expensive and time-consuming approach.

5. Treatment of Lactose Intolerance

Treatment of lactose intolerance should not be primarily aimed at reducing malabsorption but rather at
improving gastrointestinal symptoms. Restriction of lactose intake is recommended because in blinded
studies patients with self-reported lactose intolerance, even those with IBS, can ingest at least 12 g
lactose without experiencing symptoms [26,47]. Even larger doses (15 to 18 g lactose) appear to be
tolerated when dairy products are taken with other nutrients [26]. One retrospective case review reported
improvement of abdominal discomfort, with lactose restriction in up to 85% of IBS patients with lactose
malabsorption [48]; however, prospective studies show that lactose restriction alone is not sufficient for
effective symptom relief in functional GI disease [49]. In our experience this approach is effective if
symptoms are related only to dairy products; however, in IBS patients, lactose intolerance tends to be
part of a wider intolerance to poorly absorbed, fermentable oligo-, di-, monosaccharides and polyols
(FODMAPs) [9,30]. Evidence from recent trials indicates that this is present in about half of patients
with IBS and this group requires not only restriction of lactose intake, but also a low FODMAP diet
to improve gastrointestinal complaints. An initial controlled trial of a diet low in FODMAPs reported
symptom improvement in 86% of IBS patients, compared to 49% for a standard dietary intervention [50].
Three randomized controlled trials have confirmed that a low FODMAP diet can benefit a wide range of
symptoms in IBS patients [32,51,52]. All these studies included lactose restriction in the early strict
phase of the dietary intervention; however, the specific role of lactose in causing symptoms was not
assessed. A major issue with almost all dietary intervention trials is that the contribution of individual
components (e.g. lactose) is difficult to assess as other dietary components (e.g., fat [53]) can also
produce symptoms and, potentially, confound results.
Lactase enzyme replacement is another important approach in patients with isolated lactose
intolerance that wish to enjoy dairy products. One double-blind, placebo-controlled, crossover
study shows that in lactose malabsorbers with intolerance, lactase obtained from Kluyveromyces
lactis represents a valid therapeutic strategy, with objective and subjective efficacy and without side
effects [54]. Exogenous lactase obtained from Aspergillus oryzae or from Kluyveromyces lactis breaks
down lactose into glucose and galactose to allow an efficient absorption [55].
A related strategy involves probiotics that alter the intestinal flora and may have beneficial effects in
IBS patients [56]. Four-week consumption of a probiotic combination of Lactobacillus casei Shirota
and Bifidobacterium breve Yakult improved symptoms and decreased hydrogen production in lactose
intolerant patients. These effects appeared to persist for at least three months after suspension of
probiotic consumption [56]. However, in another study, milk containing Lactobacillus acidophilus
did not consistently reduce gastrointestinal symptoms in patients with self-reported lactose intolerance
compared with control participants [26]. Further studies are required to provide high quality evidence to
support or compare the efficacy of these strategies.
Nutrients 2015, 7 8029

6. Long-Term Effects of Lactose or FODMAP Restriction

Although restricting dietary lactose or FODMAPs may improve gastrointestinal complaints,

long-term effects of a diet free of dairy or FODMAPs products may be of concern [57]. Dairy products
are the major source of calcium in many individuals. No study has addressed the safety and effectiveness
of calcium replacement for patients with lactose intolerance; however, it seems reasonable to recommend
increasing calcium intake from other foods or supplements in patients that restrict intake of dairy
products, especially in the presence of other risk factors for osteoporosis.
Diet also has effects on the colonic microbiome. Altering the dietary intake of FODMAPs alter
gastrointestinal microbiota [58] and a significant decrease in the concentration of probiotic bifidobacteria
after four weeks of a low FODMAP diet has been reported [52]. Whether this change has any long-term
implications is unknown. Recommending alternative foods is a key component of patient education and
even with dietetic advice nutrient intake, in particular of calcium, can be compromised on a low lactose,
low FODMAP diet.
Another issue that should be considered is the negative effect of dietary restriction on quality of
life [9,59]. Patients with self-reported lactose intolerance restrict intake not only of dairy products but
also of other foodstuffs due to general concerns about diet and health [9,59]. This is stressful and can be
expensive as shown by the recent trend to gluten free diets [60]. Moreover, if not properly supervised,
multiple food restrictions could lead to mal- or under-nutrition. Formal dietary intervention excludes a
wide range of potential dietary triggers for a short period to achieve symptom improvement, followed by
gradual food reintroduction to identify items and threshold doses that can be tolerated by patients.

7. Conclusions

Primary lactase deficiency can be regarded as the commonest genetic disease in the World,
although, in truth, loss of lactase expression in adulthood represents the normal wild-type and lactase
persistence the abnormal mutant state. Additionally, in secondary lactase deficiency, the ability to
digest lactose can be lost due to infection, surgery and other insults. Whatever the cause, lactose
malabsorption causes symptoms by several mechanisms: unabsorbed lactose leads to osmotic diarrhea;
products of its bacterial digestion lead to secretory diarrhea and gas can distend the colon. Diagnosis
of lactose malabsorption is based on detection either of the genetic mutation, loss of lactase activity
in the enteric mucosa or evidence of malabsorption in the blood or breath. However, the presence
of lactose malabsorption does not necessarily imply that abdominal symptoms are related to this
process. The majority of healthy individuals with lactase deficiency tolerate up to 20 g lactose without
difficulty. Instead, diagnosis of lactose intolerance requires concurrent assessment of lactose digestion
and abdominal symptoms.
Recent studies have provided important new insight into the complex relationship between lactase
deficiency, lactose malabsorption and symptom generation. This work has shed light on the
wider issue of food intolerance as a cause of symptoms in irritable bowel syndrome and related
conditions. Understanding the biological mechanism for food intolerance to lactose and FODMAPs
will help clinicians make a definitive diagnosis and guide rational dietary and medical management.
Ongoing studies will provide high quality evidence to document the efficacy and long-term effects of
these strategies.
Nutrients 2015, 7 8030

Acknowledgments

We thank Hua Chu for her excellent work in the SinoSwiss trials referred to in this article.
We acknowledge funding from Nestl International that supported the Sino-Swiss trials into lactose
intolerance and digestive health.

Author Contributions

Yanyong Deng and Benjamin Misselwitz researched and drafted the manuscript. Ning Dai and Mark
Fox led many of the studies cited in this article, contributed to the draft manuscript and approved the
final publication. All authors discussed and revised all drafts and approved the final manuscript.

Conflict of Interest

Ning Dai and Mark Fox have received research funding from Nestl International for studies of lactose
intolerance. Other authors have no relevant conflicts of interest to declare.

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